1. Field of the Invention
The present invention relates to a PPAR activating compound which selectively activates, among peroxisome proliferator-activated receptors (PPARs), α-type PPAR (i.e., PPARα), and is useful as a drug for preventing and/or treating pathological conditions including hyperlipidemia, arteriosclerosis, diabetes complications of diabetes, inflammation, and heart diseases. The invention also relates to a pharmaceutical composition containing the compound.
2. Background Art
PPARs are known to form a family of nuclear receptors, and three sub-types thereof (α, γ, δ) have already been identified (Nature, 347, 645–650, 1990; Cell, 68, pp. 879–887, 1992; Cell, 97, pp. 161–163, 1999; Biochim. Biophys. Acta., 1302, pp. 93–109, 1996; and Journal of Medicinal Chemistry, 43, pp. 527–550, 2000).
Among the three sub-types, PPARα is expressed predominantly in the liver and is known to be activated by plasticizeres and/or fibrates, such as Wy 14643, clofibrate, fenofibrate, bezafibrate, or gemfibrosil (Journal of the National Cancer Institute, 90, 1702–1709, 1998, Current Opinion in Lipidology, 10, pp. 245–257, 1999).
In mammals, activation of PPARα is known to promote β oxidation of fatty acids and lower the blood triglyceride level. In humans, activation of PPARα decreases levels of blood lipids such as low-density lipoprotein (LDL) cholesterol and very low-density lipoprotein (VLDL) cholesterol. Thus, a PPARα-activator is useful as a drug for preventing and/or treating a disease such as hyperlipidemia. In addition, the PPARα-activator, is considered to be useful as a drug for preventing and/or treating pathological conditions such as arteriosclerosis due to increase the high density lipoprotein (HDL) cholesterol and the suppression of VCAM-1 (one of cell adhesion molecules). Furthermore, the PPARα-activator is considered to be useful as a drug for preventing and/or treating pathological conditions such as diabetes, inflammatory disease, and heart diseases (Journal of Atherosclerosis and Thrombosis, 3, pp. 81–89, 1996; Current Pharmaceutical Design, 3, pp. 1–14, 1997; Current Opinion in Lipidology, 10, pp. 151–159, 1999; Current Opinion in Lipidology, 10, pp. 245–257, 1999; The Lancet, 354, pp. 141–148, 1999; Journal of Medicinal Chemistry, 43, pp. 527–550, 2000; and Journal of Cardiovascular Risk, 8, pp. 195–201, 2001).
PPARγ, which is expressed predominantly in adipocytes, is known to play an important role in differentiating and proliferating adipocytes. Examples of known activators for PPARγ include thiazolidine derivative drugs such as troglitazone, pioglitazone, and rosiglitazone. These drugs are known to transform differentiated adipocytes having reduced insulin sensitivity into small adipocytes having high insulin sensitivity, to thereby improve insulin resistance (Journal of Biological Chemistry, 270, 12953–12956, 1995; Endocrinology, 137, pp. 4189–4195, 1996; Trends Endocrinol. Metab., 10, pp. 9–13, 1999; and J. Clin. Invest., 101, pp. 1354–1361, 1998). However, activation of PPARγ has been reported to have adverse effects on human to increase fat and body weight and causing obesity (The Lancet, 349, pp. 952, 1997). Recently, it has also been reported that antagonize the PPARγ possibly improves insulin resistance (Proc. Natl. Acad. Sci., 96, pp. 6102–6106, 1999; The Journal of Biological Chemistry, 275, pp. 1873–1877, 2000; and J. Clin. Invest., 108, 1001–1013, 2001).
PPARδ, which is present ubiquitously in the body, is known to take part in lipid metabolism. However, only a few high-selectivity PPARδ activators have been reported, and the biological significance of PPARδ remains unclear. At present, the structures of PPARδ activators are reported in a wide range of literature (Diabetes, 46, 1319–1327, 1997; and Journal of Medicinal Chemistry, 43, pp. 527–550, 2000). In a recent report, a PPARδ activator GW 501516 elevates HDL level in monkeys (Proc. Natl. Acad. Sci., 98, pp. 5306–5311, 2001). Moreover, adipocytes or skeletal muscle cells which are expressed activated PPARδ are reported to promote burning of fat (Cell, 113, pp. 159–170, 2003). However, a compound F, a PPARδ activator, disclosed in WO 97/28149 has an unfavorable effect of accumulating lipids in human macrophages (Journal of Biological Chemistry, 276, pp. 44258–44265, 2001). In addition, experiments using PPARδ-deficient mice indicate that activation of PPARδ induces lipid accumulation (Proc. Natl. Acad. Sci., 99, pp. 303–308, 2002). These phenomena represent two conflicting effect in terms of the progress and alleviation of arteriosclerosis. Thus, the significance of PPARδ on treatment of arteriosclerosis still remains unelucidated.
As described above, a PPARα-selective activator having low selectivity to PPARγ and to PPARδ is expected to be useful for preventing and/or treating, without causing obesity or increase in body weight, pathological conditions such as hyperlipidemia, arteriosclerosis, diabetes, complications of diabetes, inflammation, and heart diseases.
WO 02/46176 discloses a PPAR activator having a structure represented by the following formula:
(wherein each of R1 and R2 represents a hydrogen atom, a halogen atom, a nitro group, a C1–C8 alkyl group, a C1–C8 alkoxy group, or a C6–C10 aryl group, or R1 and R2, together with the carbon atoms to which they are bonded, may form a benzene ring; X represents an oxygen atom, a sulfur atom, —NR0— (R0 represents a hydrogen atom or a C1–C8 alkyl group), or —CH═CH—; G represents a single bond or a carbonyl group; R3 represents a C1–C8 alkyl group, a C2–C8 alkenyl group, a C2–C8 alkynyl group, a C3–C7 cycloalkyl group, a C1–C8 alkyl group substituted by a C3–C7 cycloalkyl group, a C6–C10 aryl group, an arylalkyl group (formed of a C6–C10 aryl moiety, with an alkyl moiety having 1 to 8 carbon atoms), a heterocyclic group, or a heterocyclicalkyl group (containing an alkyl moiety having 1 to 8 carbon atoms); n is an integer of 0 to 5; Y represents —CH2—, a carbonyl group, or —CH═CH—; Z represents an oxygen atom or a sulfur atom; p represents an integer of 0 to 5; each of R4 and R5 represents a hydrogen atom or a C1–C8 alkyl group; and W represents a carboxyl group, a C2–C8 alkoxycarbonyl group, a sulfonic acid group, a phosphonic acid group, a cyano group, or a tetrazolyl group).
WO 04/00762 discloses a PPAR activator having a structure represented by the following formula:
(wherein each of R1 and R2 represents a hydrogen atom or a C1–C3 alkyl group; X represents a single bond, CH2, or an oxygen atom; each of R3 and R4 represents a hydrogen atom, a C1–C6 alkyl group, —OCH3—, —CF3, an allyl group, or a halogen atom; X1 represents CH2, SO2, or C═O; R5 represents a C1–C6 alkyl group (which may be substituted by a C1–C6 alkoxy group or a C1–C6 alkylthio group), a C2–C6 alkenyl group, a C0–C6 alkylphenyl group (the phenyl group may have one or more substituents selected from among CF3, halogen atoms, C1–C3 alkyl groups, and C1–C3 alkoxy groups), —CO—(C1–C6 alkyl) group, or —SO2—(C1–C6 alkyl) group; and R6 represents a phenyl group or a 6-membered heteroaryl group containing one to three nitrogen atoms (the phenyl group and the heteroaryl group may be substituted by one to three functional groups selected from among C1–C6 alkyl groups, halogen atoms, —O—(C1–C6 alkyl) groups, —SO2—(C1–C3 alkyl) groups, and a phenyl group (which may be substituted by one or more functional groups selected from among halogen atoms, CF3, C1–C3 alkyl groups, —O—(C1–C3 alkyl) groups, an acetyl group, and a nitrile group)).
However, the compounds disclosed in WO 02/46176 act on any sub-type of PPARs (i.e., PPARα, PPARγ, and PPARδ), and thus are not regarded as PPARα-selective activators, whereas the compounds disclosed in WO 04/00762 are described to be preferably PPARδ-selective, and in consideration that no test data are provided therein, the compounds cannot regarded as being PPARα-selective.